Previous studies implicate Fyn, a Src family tyrosine kinase, as important for the formation of neurofibrillary tangles, one of two characteristic neuropathologies seen in Alzheimer's disease. However, whether Fyn can also affect the formation of amyloid plaques, the other neuropathological change in AD brains, is unknown. Although previous studies have indicated that the inhibition of Fyn may provide a potential therapeutic approach for decreasing neurofibrillary tangle pathology, it is important to also characterize its effects on APP processing and Abeta production. The proposed study will provide a better understanding of Fyn and its effects on APP processing and Abeta production, as well as examine the impact of Fyn in AD pathological processes, including both amyloid plaques and neurofibrillary tangles. Preliminary studies demonstrated that Fyn affects APP processing and decreases Abeta production in transiently transfected cells, indicating a positive role for Fyn in reducing Abeta pathology. This study will further investigate the mechanism by which Fyn alters APP processing and Abeta production in vitro by measuring products of APP processing in primary neuronal and glial cells cultured from Fyn+/+ and Fyn-/- mice. In addition, I will also determine whether Fyn affects APP trafficking by examining changes in localization of APP (both endogenous and transiently transfected) in Fyn primary neurons. Secondly, this study aims to investigate the effects of Fyn on Abeta production and tau phosphorylation in vivo. Physiological changes in tau phosphorylation and Abeta production will be examined in Fyn-/- mice compared to Fyn+/+ mice to determine the effect of the absence of Fyn on tau phosphorylation, as well as confirm the effect of Fyn on APP processing and Abeta production. In order to examine the impact of Fyn in the pathological process of Alzheimer's disease, Fyn-/- mice will be crossed with AD triple transgenic mice expressing mutations in APP, presenilin-1, and tau (AD 3xTg) and changes in APP processing, Abeta production, and tau phosphorylation will be measured. Lastly, to explore the potential therapeutic effect of Fyn, pharmacological and genetic Fyn inhibitors will be administered to AD 3xTg mice and changes in tau phosphorylation and Abeta production will be measured. These studies will define the effects of Fyn on APP processing and tau phosphorylation in neurons and glia in vitro and in vivo and evaluate whether inhibition of Fyn kinase is a potential therapeutic approach to AD.